Biomedical subjects

M Holdeman

Publications and source records attributed to M Holdeman.

4 recordsLinked to original sources

PubMed1985

Effects of massive doses of alpha-MSH on thermoregulation in the rabbit.

alpha-MSH-related compounds may prove to be clinically useful antipyretics since the parent peptide is extremely potent in reducing fever, it is effective when given orally, and it neither stimulates corticosteroid activity nor has marked melanotropic effects in man. To determine whether or in what doses alpha-MSH might cause harmful side-effects, we injected doses greatly exceeding those required to reduce fever into a lateral cerebral ventricle of afebrile rabbits. One hundred to seven hundred and fifty micrograms alpha-MSH caused large and prolonged reductions in body temperature and the dose-response relation was bell-shaped for both magnitude and duration. These doses caused no apparent injury to the animals. One mg alpha-MSH elicited hyperthermic responses that were variable in magnitude and duration. Animals that had previously received large doses of alpha-MSH (greater than or equal to 100 micrograms) did not develop hyperthermia, even when given 2 mg, indicating an acquired tolerance to this hyperthermic action of alpha-MSH. All animals, tolerant or previously uninjected, showed symptoms with doses greater than or equal to 1 mg alpha-MSH that included: increased salivation, agitation, ataxia, respiratory distress, and death (in 30% of the animals); those that recovered from these large doses resumed outwardly healthy appearance and behavior. Although alpha-MSH is toxic when given centrally in large doses, the 5000-fold difference between antipyretic and toxic doses indicates a wide safety margin should this peptide be used clinically as an antipyretic drug.

Animals↗

PubMed1985

Analysis of the antipyretic action of alpha-melanocyte-stimulating hormone in rabbits.

alpha-Melanocyte-stimulating hormone (alpha-MSH) or paracetamol was injected into a lateral cerebral ventricle (I.C.V.) of rabbits with elevations in rectal temperature induced by sodium arachidonate (I.C.V.), prostaglandin E2 (I.C.V.) or leucocytic pyrogen (I.V.). alpha-MSH (200 ng) was more effective than paracetamol (0.5 mg) in reducing fever caused by leucocytic pyrogen, but it did not alter hyperthermia induced by sodium arachidonate. In contrast, paracetamol reduced hyperthermic responses to arachidonate by about 70%. Neither alpha-MSH nor paracetamol affected hyperthermic responses to prostaglandin E2. The doses of alpha-MSH and paracetamol used in these experiments did not interfere with thermoregulation in a cold environment (10 degrees C). We conclude (1) that alpha-MSH and paracetamol differ in their central mechanism of antipyresis or (2) that inhibition of arachidonic acid metabolism by paracetamol is not requisite for its antipyretic effect, in which case central release of alpha-MSH may mediate the antipyretic effect of paracetamol.

Acetaminophen↗

PubMed1985

Fever-specific changes in central MSH and CRF concentrations.

The concentration of melanocyte-stimulating hormone (melanotropin; MSH) within the septal region of the brain increases during the fever, and septal injections of MSH are antipyretic. Corticotropin-releasing factor (CRF), when injected intracerebroventricularly, is also antipyretic. Using sensitive radioimmunoassays of microdissected tissue extracts, we established the presence of immunoreactive MSH (IRMSH) and CRF (IRCRF) within discrete central nervous system sites of the rabbit. Leukocytic pyrogen-induced fever and hyperthermia due to heat exposure did not alter concentrations of IRMSH or IRCRF in tissue extracted from preoptic-anterior hypothalamic or midbrain central gray regions. However, significantly greater levels of IRMSH were detected in septal extracts of febrile rabbits than in similar extracts from afebrile controls or heat-stressed animals. A significant decrease in IRCRF was detected in paraventricular nucleus extracts from febrile animals compared with extracts from afebrile controls or heat-stressed rabbits. Our results support the hypothesis that these central peptides have a role in temperature control during fever. Since no changes were detected in extracts from hyperthermic rabbits, it appears that changes in concentration of these neuropeptides within particular brain regions are specific to the febrile state and are not caused by elevation of body temperature or by nonspecific stress.

Animals↗

PubMedDate not supplied

Antipyretic activity of a potent alpha-MSH analog.

[Nle4,D-Phe7]-alpha-MSH has exceptional potency in certain biological assays of alpha-MSH activity such as skin darkening in frogs. However, this analog was equipotent to alpha-MSH in induction of grooming in the rat and had opposite effects on the performance of a visual discrimination task. These results led to the suggestion that distinct differences may exist between the melanocyte and CNS receptors for alpha-MSH. We determined the antipyretic and hypothermic potencies of centrally and peripherally administered [Nle4,D-Phe7]-alpha-MSH, relative to those of alpha-MSH, in the rabbit. Central injections of 40 and 80 ng of [Nle4,D-Phe7]-alpha-MSH caused hypothermia in afebrile rabbits, whereas 20 and 10 ng, which had no effect on afebrile body temperature, caused greater than 40% reduction in leukocytic pyrogen-induced fever. These results indicate that this analog is approximately 10 times more potent in reducing fever than alpha-MSH, making it the most potent antipyretic substance yet described. In contrast, IV administration of 16 micrograms of the analog, an extremely large dose relative to established antipyretic doses of alpha-MSH, elicited weak, variable responses. Since this analog is said to be resistant to degradation by serum enzymes, the contrast between the effects of central and peripheral administration may reflect a limited ability of the analog to cross the blood brain barrier when given IV. Our results do not suggest any distinct differences between the melanocyte receptors for alpha-MSH and those involved with CNS control of temperature. The marked central potency of [Nle4,D-Phe7]-alpha-MSH could result from an increased duration of action and/or a greater affinity for central receptor sites relative to alpha-MSH.

Animals↗